1. The Field of the Invention
The present invention is concerned with a method of enhancing the activity of phagocytes in warm blooded animals. The invention is also concerned with a method of modulating the cellular or humoral immune response system of a warm blooded animal and, in still another variant, with a method of reducing the adverse effects of stress on the foregoing defense mechanisms of warm blooded animals.
2. The Prior Art
The defense mechanisms of warm blooded animals providing non-specific resistance and/or cellular or humoral immunity to invading living disease producing micro-organisms, viruses and other pathogens are well known and are described in a large number of publications. Examples of publications which are especially pertinent include an article entitled "Secretory Function of Mononuclear Phagocytes," The American Journal of Pathology, Volume 83, Pages 396 et. seq., (1976); an article entitled "Regulation of Immunity and Inflammation by Mediators from Macrophages," The American Journal of Pathology, Volume 85, Pages 465 et. seq. (1976); an article entitled "Cytotoxic Macrophages: A Rapid Nonspecific Response to Viral Infection," The Journal of Immunology, Volume 117, Pages 2067 et. seq. (1976); and the various publications cited and referred to therein, all of which including the citations are incorporated herein by reference.
As is discussed in the aforementioned publications, it is generally accepted that a warm blooded animal's first line of defense against a cancer cell or against an invading microorganism, be it bacterium, fungus, protozoa, virus, or other pathogen, in the absence of previously acquired cellular or humoral immunity, involves non-specific cellular defense mechanisms. Prominent among these defending cells are the blood-borne and local or tissue phagocytes, including macrophages and their precursor monocytes, and phagocytes of a relatively short life span such as neutrophils, polymorphonuclear leukocytes or microphages.
Examples of other cells and substances involved in specific immunity include T-lymphocytes, B-lymphocytes and antibodies produced thereby. In the normal sequence of events, the non-specific phagocytes including macrophages in a highly cytotoxic activated state appear on the first day an animal is infected and increase until the second or third day of the infection. Specifically sensitized highly activated T-lymphocytes usually appear on the third day following infection, and increase in numbers until approximately the sixth day. Antibodies and other components of the humoral immune response system usually appear on the fourth day following infection and increase until approximately the eighth day.
The phagocytes and especially the monocyte macrophage system of cells perform other important functions in addition to the phagocytosis and destruction of invading microorganisms and cancer cells.
It is thought that two interrelated functions of macrophages in immunologic processes are to concentrate and remove antigen and to present certain substances for recognition to T-lymphocytes and/or B-lymphocytes. The association of an antigen with macrophages appears to be an early and important step in building up a complete immune response through the lymphocytes. The macrophages also secrete substances which have the capacity to enhance, reduce or otherwise change the response of the lymphocytes. The macrophages serve as the main effector cells and modulate the immune processes either up or down in accordance with their own state or degree of activation through interactions with the lymphocytes and especially with the T-lymphocytes.
The activity of macrophages may be modulated either up or down. Prior to infection of the warm blooded animal, they may exist in a normal, basal or depressed state of activation and in these states they do not have a pronounced modulating effect on the immune response system. The phagocytes and especially the macrophages, are capable of being activated when challenged by diverse invading microorganisms, by secretions from the T-lymphocytes, or by certain chemicals. The resulting activated macrophages are characterized by a markedly increased phagocytic activity, an increased content of acid hydrolyases, a more active metabolism, an increased microbicidal capacity, and a increased rate of secreting immunomodulating substances. The importance of the state of activation of the macrophages, as well as the importance of the state of activation of the components of the cellular and humoral immune response systems, are well known and recognized in this art and are described in the aforementioned publications. The capacity of compounds of the invention to enhance the microbicidal activity of macrophages that are at rest, that may be depressed by other drug therapies as adrenocorticosteroids, or that are already non-specifically activated in response to infection results from the special capacity of compounds of the invention to increase the generation of intracellular microbicidal enzymes and to increase the generation and efficiency of utilization of microbe-oxidizing substrates such as hydrogen peroxide, superoxide, etc. It is known that the phagocytes and especially the macrophages, T-lymphocytes, B-lymphocytes and other components of the cellular and humoral immune response systems must be stimulated in order to function most effectively and to provide optimum resistance to invading microorganisms and cancer cells. However, it is possible for the cellular and/or humoral immune response systems to become too highly activated due to a failure of feedback control as the generation of depressor T-cell signals or depressor macrophage signals. In this hypersensitive condition, the immune functions can be enhanced excessively for certain antigens, as in allergies such as hay fever and in autoimmune type diseases including rheumatoid arthritis and the like.
Immunity and inflammation are regulated by mediators from phagocytes and especially macrophages, and also by mediators from T-lymphocytes and other components of the cellular and/or humoral immune response systems. It has been established that certain cells emit positive control signals and enhance the activity of phagocytes and/or the immune responses, whereas still other cells emit negative control signals and decrease the activity of phagocytes and/or the immune responses. Thus, it is apparent that a method capable of modulating the activity of phagocytes and/or the cellular and/or humoral immune response systems within the ranges sufficiently high to assure adequate resistance to invading disease producing micro-organisms and cancer cells, and yet within ranges providing a sufficiently low state of activation to prevent or suppress diseases or conditions resulting from a hypersensitive cellular or humoral immune response system such as allergies and autoimmune diseases, would be of great benefit. However, an entirely satisfactory method was not available prior to the present invention whereby these desired benefits could be achieved with drugs which are non-toxic and free of side effects.